Normal keratinization is accompanied by striking changes in epidermal lipid content and distribution. Recently, it has become apparent that aberrations in lipid metabolism, whether produced by genetic disorders of lipid metabolism or drugs, are associated with abnormal keratinization (ichthyosis). More common human scaling disorders, such as psoriasis and chronic eczema, have also been associated with alterations in epidermal lipids. The candidate's goal is to elucidate the role of epidermal lipids in the pathogensis of human scaling skin diseases. I intend: 1) to characterize epidermal lipids in human genetic disorders of keratinization. I suspect that specific abnormalities in epidermal lipid composition will be found in several of these disorders. These abnormalities should yield clues both to the responsible enzymatic defect in lipid metabolism (as I have found in x-linked ichthyosis where absence of steroid sulfatase leads to accumulation of cholesterol sulfate in scale) and to novel topical therapies to correct these abnormalities. 2) To correlate lipid biochemical information obtained by thin layer and gas liquid chromoto graphy, with morphological anaylsis of lipid distribution by lipid histochemistry, fluorescent microscopy, and lectin cytochemistry. These combined biochemical and histo chemical studies should result in objective methods for the diagnosis of many of these genetic disorders, which currently can only be classified by clinical assessment. 3) To make functional correlations by comparing the ability of normal and abnormal stratum corneum lipid extracts to form liposomes. These studies may aid in understanding how alterations in epidermal lipid composition lead to scaling, and may provide an in vitro assay for the "stickiness" of skin lipids. 4) To utilize epidermal tissue cultures of these disorders to delineate these enzymatic defects, and to study regulatory and corrective influences. 5) To develop animal models with drugs that are known to produce scaling disorders in humans. These analogues should provide opportunities to study modulations in lipid composition under controlled conditions, as well as serving as subjects for pre-clinical testing of novel therapies. Finally, since retinoids profoundly improve many clinical disorders of keratinization, their impact on epidermal lipid composition will be assessed.